Osteoporosis, or porous bone of low mass, is a disease characterized by inadequate bone density and structural deterioration of trabecular bone. This can lead to bone fragility and an increased susceptibility to fractures of the hip, spine and wrist. Osteoporosis, like high blood pressure, is a “silent disease” because bone loss occurs without symptoms and over a long period of time. People are frequently unaware they have osteoporosis until their bones become so weak that a sudden bump or fall causes a fracture or a vertebra to collapse. Osteoporosis is associated with high morbidity and poor quality of life.
The two primary bone cells are the osteoclasts and the osteoblasts. The osteoclasts are the cells that resorb, or breakdown, bone. They are of haemopoietic origin and develop from stem cells in the bone marrow. Mature functional osteoclasts are multinuclear cells and are localized on mineralized bone surfaces that these specialized cells can resorb. The osteoblasts, which are of mesenchymal origin, are the cells that build up bone. When the osteoblasts are finally encased in the mineralized matrix, the end stage phenotype, they are called osteocytes. The osteocytes are mechanosensory cells and respond to mechanical loading by generating signals for osteoclasts and osteoblasts lining the bone surface.
Bone is mainly built during foetal life, youth and adolescence. Once bones are formed, their shape and structure are continually renovated and modified by two processes known as modeling and remodelling. Both modeling and remodelling result in the replacement of old bone by new bone.
Modeling takes place during an individual's growth and is the main process through which the skeleton increases its volume and mass. In modeling, new bone is formed at a different location than where the bone was broken down. This results in a change in the shape of the skeleton and also is the cause for the increase in bone size. Depending on the lifestyle and dietary intake, bone mass can further increase until around the age of 30. This is called peak bone mass. Bone mass will stay more or less constant until around the age of 40 to 45. Thereafter, bone mass will decline gradually due to aging or rapidly, as in the case of post-menopausal osteoporosis.
The resorption of bone by osteoclasts and the subsequent formation by osteoblasts is called remodelling. This process takes place in an orderly fashion beginning with bone being eroded by osteoclasts, followed by refilling by osteoblasts at the resorption sites. In order to maintain bone mass constant bone resorption and bone formation are tightly coupled, a phenomenon called coupling. The molecular mechanisms responsible for this are still unclear. The remodelling process replaces old bone by new, ensures the correction of possible microdamages and enables the regulation of mineral homeostasis. During life, bone is remodelled constantly, but in healthy adults, a quantitative and qualitative balance is kept between bone formation and bone resorption to maintain bone mass constant. During aging or under certain pathological conditions, the balance between bone resorption and formation is disturbed leading to a gradual decrease in bone mass (as seen in old age osteoporosis) or to a rapid bone loss and destruction of bone architecture (as seen in post-menopausal osteoporosis).
In normal healthy individuals, the amount of bone formed during bone remodelling equals the amount of bone destroyed in order to maintain bone mass constant. When more bone is destroyed than formed bone loss occurs and bone diseases, such as osteoporosis, may develop. Osteoporosis is a crippling disease principally affecting the elderly and is characterized by low bone density leading to fractures and associated with high morbidity. The current FDA-approved drugs available only slow down bone loss or prevent further loss. Most drugs used to treat low bone mass are aimed at stopping the loss, not regaining bone density. This is due to the lack of understanding and knowledge of the molecular mechanisms of bone remodelling.
Conversely, when more bone is deposited than is destroyed, a phenotype of sclerosteosis may arise as seen, for example, in Simpson-Golabi-Behmel syndrome (SGBS), characterised by enlarged bones, most noticeably of the face. In SGBS, the patient typically presents with a broad, stocky appearance, large protruding jaw, widened nasal bridge and upturned nasal bridge. Infant mortality is high in SGBS patients, and early cardiac arrest is common in adults. No treatment for such sclerosteosis phenotype is available.
The present invention aims to provide compositions, method of treatment and methods of diagnosis of disorders related to abnormal bone density, which overcome the problems in the art.